In Korea, dietary fat intake has recently increased with the growth of economy and the westernization of diet life, and onset of metabolic diseases such as obesity, diabetes, hyperlipidemia, hypertension, arteriosclerosis, and fatty liver increased due to insufficient exercise. In addition, obesity is an aesthetic problem to people who generally tend to prefer to slim body types as well as being associated with various disorders.
To date, therapeutic agents for obesity may be largely divided into drugs that act on the central nervous system to affect appetite and drugs that act on the gastrointestinal tract to inhibit uptake. Drugs acting on the central nervous system were placed on the market as anti-obesity drugs which work on the serotonin (5-HT) in the nervous system such as fenfluramine, dexfenfluramine and the like, on the noradrenaline nervous system such as ephedrine and caffeine, and on both the serotonin and the noradrenaline nervous system such as recently developed sibutramine, as classified by acting mechanisms. Representative of anti-obesity drugs acting on the gastrointestinal tract is orlistat, approved as a therapeutic agent for obesity, which inhibits intestinal lipase to reduce fat uptake. There are problems with some of the pre-existing drugs. For example, fenfluramine and the like have been prohibited from being marketed due to the side effect of incurring primary pulmonary hypertension or valvular heart disease, and other drugs cannot be applied to patients with heart failure or kidney failure due to the occurrence of blood pressure reduction or lactic acidosis.
Diabetes is a group of metabolic disorders caused when insulin is insufficiently secreted or in does that do not enable normal function (DeFronzo, 1988) and is characterized by hyperglycemia, that is, high blood sugar levels over a prolonged period, which causes various symptoms and syndromes, with glucose in urine. In recent years, the prevalence of obesity, particularly, abdominal obesity has increased, leading to the explosion of the prevalence of diabetes.
As of 2000, diabetes patients were estimated to be 170 million worldwide and expected to increase to 370 million people in 2030. However, a 2008 analysis report showed that the number of diabetes patients may have already reached 350 million worldwide (Danaei et al., 2011), with far more significant aggregation than expectation. It is reported that more than about 80% of type 1 diabetes patients are obese whereas only less than 10% of (non-)obese patients have diabetes (Harris et al. 1987). The correlation between diabetes and obesity is attributed to the fact that adipokines and free fatty acids are irregularly secreted to induce fatty acids to accumulate in insulin-sensitive tissues such as beta cells, kidneys, liver, heart, etc., resulting in lipotoxicity. If left without suitable treatment, chronic hyperglycemia may be prone to incurring various pathological symptoms including retinopathy, renal dysfunction, neuropathy, and vascular disorder. Indispensable for preventing such complications is effective blood sugar management.
Nowadays, the control of blood sugar levels is accomplished by lifestyle improvement (diet therapy, exercise therapy), and medications. However, diet therapy or exercise therapy is difficult to strictly manage and practice, with limitations of the effects thereof. Hence, most patients with diabetes rely on the control of blood sugar levels by medications such as insulin, insulin secretagogues, insulin sensitizer, and hypoglycemic agents, as well as lifestyle improvement.
Insulin produced using a recombinant method is used as a drug indispensable to type 1 diabetes patients and type 2 diabetes patients which fail to control blood sugar levels, and is advantageous in blood sugar control. However, it suffers from the disadvantage of repulsion to syringe needles, difficulty in administration, hypoglycemic risk, and weight gain.
Meglitinides, a kinds of insulin secretagogues, are short-acting agents and are taken before meals. Among them are NovoNorm (repaglinide), Fastic (nateglinide), and Glufast (mitiglinide). Insulin sensitizers are characterized by almost no hyperglycemic incurrence when taken alone, and may be exemplified by biguanide drugs, such as metformin, and thiazolidinedione drugs such as Avanida (rosiglitazone) and Actos (pioglitazone).
Recently, GLP-1 agonists have been developed using the action of glucagon-like peptide-1, which is an insulin secretion-stimulating hormone, and include exenatide and Victoza (liraglutide). In addition, DDP-4 inhibitors, which inhibit the action of DPP (dipeptidyl peptidase-4), an enzyme responsible for the rapid inactivation of GLP-1, are newly developed drugs and are representatively exemplified by Januvia (ingredient name: sitagliptin). However, those drugs are reported to have side effects of hepatoxicity, gastrointestinal disorders, cardiovascular disorders, and carcinogenicity. Another problem with the drugs is a high annual treatment cost, which is a barrier to the treatment of diabetes. Indeed, health care costs of pre-diabetes and diabetes approached about 200 trillion won in the USA as of 2007 (Dall et al., 2010), and health care costs of obesity are also near 150 trillion won only in the USA as of 2008 (Finkelstein et al., 2009). Therefore there is an urgent need for the development of a drug that can effectively lower blood glucose levels and can be applied to both diabetes and obesity-induced diabetes, with less side effects.
For this, the present inventors have recently paid attention to energy metabolism-regulating mechanisms in order to find an improved method for the treatment of obesity, and have made research of signals responsible for lipid accumulation and proteins affecting lipid accumulation upon the intake of high-fat diets in humans, with the premise that the compound to be developed should of higher safety (lower toxicity). As a result of research on signals for suppressing the expression of proteins responsible for fat accumulation and for degrading accumulated fat and on proteins involved in the signaling, the present inventors succeeded in developing peptides that promote lipolysis. In addition, the peptides of the present invention exhibit outstanding therapeutic efficacy on diabetes and obesity-induced diabetes. The fat accumulation induced by high-fat diets, the suppression of insulin signaling attributed to fat accumulation in the liver or muscle, and resulting insulin tolerance are causes of diabetes. Each and complexes of the peptides according to the present invention are therapeutically effective for such diabetes and obesity-induced diabetes.
Throughout this specification, reference is made to many papers and patent documents, with citations thereof indicated. The disclosures of the cited papers and patent documents are herein entirely incorporated by reference and thus the level of technical field to which the present invention belong and contents of the present invention are explained more definitely.